Perfusion Cell Culture is Gaining Ground Upstream

Published on: 
BioPharm International, BioPharm International, November 2021, Volume 34, Issue 11
Pages: 20–21

The adoption of perfusion cell culture continues to advance with the help of PAT tools.

The establishment of perfusion cell culture in upstream processing is an ongoing shift in the biomanufacturing industry. Earlier reluctance to adopt a perfusion-based system stemmed largely from uncertainty surrounding process monitoring and control, but advancements in process analytical technology (PAT) tools are making it easier to monitor and control continuous bioprocessing. But what progress has been made so far in establishing perfusion cell culture at both the clinical manufacturing scale and commercial level?

Gaining an increasing toehold

How much of a toehold does perfusion cell culture have in clinical and commercial upstream processing today? Has the earlier hesitation and reluctance given way to further adoption of this technology? Priyanka Gupta, head of Market Entry Strategy, Protein Segment, at Sartorius explains that more companies are adopting perfusion cell culture in upstream bioprocessing as the industry comes to realize the gains perfusion offers in volumetric productivity.

“In general, there are various companies (both in CDMO/CMO [contract development and manufacturing organization/contract manufacturing organization] and the mid–large company space) adopting perfusion scales from 50–500 L for clinical and commercial production,” Gupta says. Gupta points out that companies are also realizing not just productivity gains but time, footprint, and sustainability advantages by using perfusion. Nowadays, even large companies that require larger throughput are looking into using 1000-L and 2000-L stirred tank reactor (STR) scales for perfusion.

Gupta notes that, although the fed-batch method of cell culture still dominates, perfusion is gaining much more adoption as the industry comes to realize how perfusion can cater to future manufacturing needs, including a smaller footprint and having sustainable high productive facilities.

Advancement of PAT tools

PAT tools are important for making the adoption of perfusion cell culture easier and enabling continuous bioprocessing. Perfusion can be challenging at first to run and understand, and PAT tools play a key role in developing the perfusion process, says Gupta. Having these tools both at process development and manufacturing scales has made the adoption of perfusion more feasible. “The pharma industry has been using perfusion for a while, but now with the advantages and having the right tools, the combination of PAT and systems has also made the biopharma industry adopt it with confidence,” Gupta states.

For one thing, PAT tools enable understanding of the process earlier in the process development stage, which in return is important to having ease of scale-up, mitigating risks, and knowing the critical process parameters, Gupta explains.

There have been advances in PAT tools on several fronts. One area has been the transfer of established sensors and control strategies from a stainless-steel environment to the single-use environment. This transfer has enabled the switchover to more modern perfusion processes. Meanwhile, the advancement of spectroscopic technologies for inline analysis has also contributed to easing the use of perfusion. A number of PAT tools already used in bioprocessing make use of spectroscopy. Advances in data analytics is another ongoing development that supports perfusion processes because data analytics today are capable of processing the vast amounts of data generated by modern PAT tools (1).


Challenges remain

However, despite the many advances in PAT tools, there are still challenges to perfusion adoption. A lack of expertise and a sense of comfort in new technologies often leave companies with hesitation to adopt a new process, for example. Gupta observes that, with perfusion, usually the product quality could be “better” than a normal fed-batch process. However, this requires explanation that perfusion will not have any negative impact on drug efficacy, especially if a company has already filed an investigational new drug application or has done clinical trials.

“Clarification is another aspect that needs to be understood,” says Gupta. “Having high cell densities resulting from perfusion will impact your clarification, and one needs to really understand the capacity and scale up of clarification technologies. Another important consideration is the media requirement due to perfusion. To get higher volumetric productivity, it is necessary to understand what kind of media exchange rate is needed. This in turn can increase the amount of media required. It becomes a balance between productivity and an increase in cost and risk mitigation of media management.”

Perfusion cell culture also has the benefit of operating at steady-state conditions for extended periods of time, which results in more consistent and higher product quality, but maintaining a steady state requires effective process monitoring and control. However, real-time data collection is not always a simple task. The key challenges associated with process monitoring include monitoring the accurate concentration of cells, keeping track of the main nutrients and metabolites, and monitoring the relationship between growth and metabolic data, which is done using typical in-line, real-time monitoring of important parameters such as pH, temperature, and dissolved oxygen (1).

Continuous bioprocessing shift

Overall, perfusion cell culture is showing positive outcomes, which may bode well for a more determinate shift to continuous bioprocessing in the future. Because perfusion-based processes offer many advantages, such as higher volumetric productivity, smaller modular facilities, lower cost, and more sustainable facilities, a fully continuous process is desired, reveals Gupta. “Having a facility with continuous processing, the industry can realize a fully controlled, automated closed process, which would simplify both processing and drug demands. Continuous processing eliminates the need for hold steps and a lot of manual intervention, and results in increased process robustness,” Gupta states. Although there are still technology developments that need to happen to realize this, the industry is moving toward this goal step by step, she asserts.

Furthermore, support for continuous bioprocessing from regulatory authorities, as well as encouragement and guidance for improving process control and consistency, have helped to enable the industry to drive advances in PAT tools. This regulatory support in turn has eased the path for the implementation of novel solutions into perfusion processes (1).

Expansions set for future needs

The industry is also seeing investment in perfusion capacity in response to the growing demand for biologics. In late December 2020, WuXi Biologics announced its acquisition of Bayer’s drug substance manufacturing facility in Wuppertal, Germany. The facility includes three 1000-L perfusion bioreactors in addition to six 2000-L fed-batch bioreactors for biologics and vaccines, which are expected to be ready for good manufacturing practice (GMP) operations in late 2021 (2).

In addition, Abzena opened a new biologics GMP manufacturing site—the company’s sixth global manufacturing site—in the United States, which it announced in January 2021. The new site will accommodate Phase III and commercial manufacturing and will be equipped for existing and new advances in manufacturing, including continuous manufacturing and perfusion. Manufacturing operations are planned to start in mid-2022 (3).


1. C. Challener, BioPharm International 33 (11) 16–19 (2020).
2. WuXi Biologics, “WuXi Biologics to Acquire Drug Substance Facility in Wuppertal, Germany from Bayer,” Press Release, Dec. 21, 2020.
3. Abzena, “Abzena Announces Opening of New Biologics GMP Manufacturing Site with Up to 12 X 2000-L Bioreactors,” Press Release, January 2021.

About the author

Feliza Mirasol is the science editor for BioPharm International.

Article Details

BioPharm International
Vol. 34, No. 11
November 2021
Pages: 20–21


When referring to this article, please cite it as F. Mirasol, “Perfusion Cell Culture is Gaining Ground Upstream,” BioPharm International 34 (11) 20–21 (2021).